Biology subjects

Hall, G. T.

Publications and source records attributed to Hall, G. T..

5 recordsLinked to original sources

bioRxiv2026

Recurrent leukaemia stem cell states define the antigenic landscape of paediatric Acute Myeloid Leukaemia

Paediatric acute myeloid leukaemia (pAML) remains a leading cause of childhood cancer mortality, with disease heterogeneity representing a major obstacle to effective immunotherapy. To enable rational immunotherapy design accounting for such heterogeneity, we combined single-cell transcriptomics and surface proteomics (CITE-seq). Using an integrated framework for malignant cell identification and unbiased gene program identification, we resolved three conserved leukaemia stem cell (LSC) subtypes, primitive (P-LSC), monocytic (M-LSC), and erythroid-like (E-LSC), that frequently coexist within individual patients in varying proportions and represent distinct stem-cell states with characteristic immunophenotypes and transcriptional programmes. Quantitative surface antigen profiling revealed that no single target achieved full LSC coverage. CLEC12A, an antigen currently being evaluated clinically, was expressed across P-LSC and M-LSC but was largely absent from E-LSC. In contrast, CD84 provided complementary coverage in the P and M groups and served as the primary target in the E-LSC population. The combination of CLEC12A and CD84 provided broad coverage across all three LSC subtypes, while sparing healthy haematopoietic stem cells. Validation across independent single-cell and bulk cohorts confirmed the robustness of this combination. These findings establish a paediatric-specific framework for antigen prioritisation in AML, identify CLEC12A/CD84 as a robust dual-targeting strategy across heterogeneous LSC states, and provide a blueprint for the rational design of next-generation CAR T-cell combinations.

cancer biology↗

bioRxiv2025

The challenges of single cell transcriptomics on difficult human tissue: the placenta

Demand for the application of single cell transcriptomics on difficult tissues, processed and stored in disparate conditions, has led to the development of various single cell modalities. We focus on the placenta, a challenging tissue to transcriptomically interrogate due to senescence, intermittent hypoxia, high levels of RNase activity and tissue trauma at delivery. We performed single cell and nuclei transcriptomics on two samples with probe-based and native molecule transcript capture, droplet based and in situ plate based cell isolation. We explored sample and storage variations, including freshly dissociated tissues, fixed cells, snap frozen and FFPE processing. We find that variations in sample processing and storage have much larger effect on cell type proportions than differences in chemistry, impacting the biology that can be learned or the identification of disease markers. Further, the transcriptomic output of in situ combinatorial indexing consistently overlaps, with single nucleus transcriptomics, sharing little with other modalities. This may limit combinatorial indexing for sampling cytoplasmstic mRNAs. Our comprehensive analysis of the varying effect of single cell transcriptomic modalities, including their sample management strategies, provides novel and essential considerations for the experimental design and analysis of single cell transcriptomics applicable to challenging tissues, offering actionable guidance for future experiments. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=76 SRC="FIGDIR/small/688483v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@a0767forg.highwire.dtl.DTLVardef@c3af0corg.highwire.dtl.DTLVardef@1193e3eorg.highwire.dtl.DTLVardef@45989c_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2024

An in vivo and in vitro spatiotemporal atlas of human midbrain development

The dopaminergic system has key roles in human physiology and is implicated in a broad range of neurological and neuropsychiatric conditions that are increasingly investigated using induced pluripotent stem cell-derived midbrain models. To determine the similarity of such models to human systems, we undertook single cell and spatial profiling of first and second trimester fetal midbrain and compared it to in vitro midbrain models. Our initial histological analysis of second trimester fetal midbrain revealed structural complexity already similar to that of adult tissue, although this similarity did not fully extend to transcriptional activity. Moreover, we show that in vitro models recapitulate the transcriptional activity of late first trimester fetal midbrain, while 3D models replicate the spatial organization and cellular microenvironments of first and second trimester fetal midbrain. Understanding the extent of human tissue recapitulation in midbrain laboratory models is essential to justify their use as biological proxies.

neuroscience↗

bioRxiv2023

Dawnn: single-cell differential abundance with neural networks

Analysis of single-cell transcriptomes can identify cell populations more abundant in one sample or condition than another. However, existing methods to discover them suffer from either low discovery rates or high rates of false positives. We introduce Dawnn, a deep neural network able to find differential abundance with higher accuracy than current tools, both on simulated and biological datasets. Further, we demonstrate that Dawnn recovers published findings and discovers more cells in regions of differential abundance than existing methods, both in abundant and rare cell types, promising novel biological insights at single-cell resolution.

bioinformatics↗

bioRxiv2022

Short-term Rho-associated kinase inhibitor treatment accelerates primary keratinocyte growth while preserving stem cell characteristics

Somatic stem cells can be cultured in-vitro and are attractive for cell and gene therapies, but their slow growth in in-vitro culture affects survival and stemness and hinders clinical applications. Rho-associated kinase inhibitor (ROCKi) has been used to overcome these obstacles. However, it risks changing the characteristics of stem cells. We found that primary keratinocyte stem cells (KSCs) cultured with the ROCKi Y-27632 for six days exhibited rapid proliferation while maintaining the ability to differentiate. Importantly, after discontinuation of ROCKi treatment, KSC numbers and characteristics were indistinguishable from those in non-treated cultures. We further confirmed that ROCKi treatment resulted in the activation of AKT and ERK pathways, which could support cell survival and proliferation in keratinocytes. We thus concluded that accelerating keratinocyte expansion with short-term ROCKi treatment does not exhaust KSCs self-renewal and differentiation capacities, presenting a safe avenue for clinical applications.

cell biology↗